Cephalosporins

ABSTRACT

Cephalosporins represented by the formula 
     
         X--S--Y 
    
     wherein X is a deacetoxycephalosporinyl group and Y is a 6-membered heterocyclic group containing 1-3 nitrogens at least one of which is substituted and at least one of which is adjacent to a carbonyl group, said heterocyclic group containing one or more ring substituents and being characterized by being non-aromatic and non enolizable to an aromatic form.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of U.S. Application Ser.No. 586,677, filed June 13, 1975, now U.S. Pat. No. 4,091,211, issuedMay 23, 1978.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to cephalosporins represented by thegeneral formula

    X--S--Y

wherein X is a deacetoxycephalosporinyl group and Y is a 6-memberedheterocyclic group containing 1-3 nitrogens at least one of which issubstituted and at least one of which is adjacent to a carbonyl group,said group containing one or more ring substituents and beingcharacterized by being non-aromatic and not enolizable to an aromaticform and pharmaceutically acceptable salts and hydrated forms thereof.

A preferred group of compounds in accordance with the present inventionare those wherein X in formula I is a group represented by the formula##STR1## wherein R₁ is hydrogen or methoxy, R₂ is cyano, or apyridylthio, aliphatic, alicyclic, aromatic or hetero aromatic groupwhich may be substituted with one or more members of the groupconsisting of hydroxy, halo, lower alkyl or lower alkoxy groups and R₃is hydrogen, hydroxy, hydroxymethyl, amino, azido, carboxy or sulfo and,when R₂ is a pyridylthio group, R₃ is hydrogen.

As used herein, the term "halogen" denotes chlorine, fluorine orbromine, chlorine being preferred. As used herein, the term "aliphaticgroup" includes both straight and branched chain alkyl and alkenylgroups with up to 6 carbon atom such as, for example, methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl and the like, vinyl,propenyl, butenyl, pentenyl, hexenyl and the like; the alkyl groups with4 carbon atoms, particularly n-butyl and isobutyl, being preferred. Theterm "alicyclic group" denotes saturated or unsaturated, non-aromaticgroups containing from 3 to 6 carbon atoms such as, for example,,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cyclohexadienyl and the like; the groups containing 6 carbon atoms,particularly cyclohexyl and cyclohexadienyl, being preferred. As usedherein, the term "aromatic group" relates to phenyl, phenyl-C₁₋₃ -alkyland phenoxy-C₁₋₃ -alkyl, wherein the phenyl and/or the alkyl moiety maybe substituted with one or more members of the group consisting ofhydroxy, halo, lower alkyl or lower alkoxy; phenyl and p-hydroxyphenylbeing preferred. The term "heteroaromatic group" relates to 5- or6-membered aromatic groups containing 1-4 nitrogen atoms and/or oneoxygen or sulfur atom such as for example, sydnonyl, tetrazolyl, furyl,thienyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl and the like, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl and the like; the 5-membered groups, particularly thienyl,furyl, tetrazolyl, triazolyl, pyrazolyl and sydnonyl being preferred.

Most preferred compounds in accordance with the invention are those inwhich R₂ is cyano, 2-thienyl, 2-furyl, phenyl, cyclohexyl, 1-tetrazolyl,1-triazolyl, 1-pyrazolyl, 3-sydnonyl or 4-pyridylthio with the provisothat, wherein R₂ is any of the latter five groups, R₃ is hydrogen.

Preferred compounds of formula I are those wherein Y is a non-aromaticpyridonyl, pyrimidonyl, pyrazonyl, pyridazonyl or triazonyl groupcontaining substitution on one or more members of the ring with theproviso that at least one nitrogen is substituted.

Examples of specific groups represented by Y in the above formula inaccordance with the invention include the following:

2-oxopyridin-4-yl;

a 2-oxopyrimidin-4-yl group such as, for example, 1-amino, 1-ethyl- or1-butoxy-1,2-dihydro-2-oxopyrimidin-4-yl or1-butoxy-1,2-dihydro-5-methyl-2-oxopyrimidin-4-yl;

a 4-oxopyrimidin-2-yl group such as, for example,1-ethyl-1,4-dihydro-6-methyl-4-oxopyrimidin-2-yl or1,4-dimethyl-1,6-dihydro-6-oxopyrimidin-2-yl;

2,6-dioxopyrimidin-4-yl;

2-oxopyrazin-3-yl;

2,3,5-trioxopyrazinyl-6-yl;

3-oxopyridazin-6-yl;

3-oxopyridazin-4-yl;

a 5,6-dioxo-as-triazin-3-yl group such as, for example, 4-ethyl-,4-methyl-4-allyl-, 4-butyl-, 4-(2-methoxyethyl)-, 1,4-dimethyl- or1,4-diethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl or1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl;

2-oxotriazin-4-yl; or

2,4-dioxotriazin-6-yl.

In accordance with the invention, substituents on the nitrogen atoms inthe heterocyclic ring represented by Y in formula I are selected fromthe group consisting of lower alkyl, lower alkenyl, lower alkynyl,cycloalkyl, hydroxy, lower alkoxy, amino, mono(lower alkyl)amino,di(lower alkyl)amino, formyl, lower alkanoyl, lower alkanoylamino,carbamoyl, mono(lower alkyl)aminocarbonyl and di(loweralkyl)aminocarbonyl.

Wherein in accordance with the invention, the heterocyclic ringrepresented by Y in formula I is substituted on the ring carbon atoms,such substituents are selected from the group consisting of lower alkyl,lower alkoxy, amino, mono(lower alkyl)amino, di(lower alkyl)amino, loweralkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(loweralkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano and halogen.

Wherein either ring nitrogen or carbon atoms in the heterocyclic ringrepresented by Y in formula I are substituted by lower alkyl groups,said groups may in turn be substituted with a member selected from thegroup consisting of hydroxy, lower alkoxy, amino, mono(loweralkyl)amino, di(lower alkyl)amino, formyl, lower alkanoyl, loweralkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono(loweralkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, cyano, halogen andepoxy.

In accordance with the present invention, the terms "lower alkyl","lower alkenyl" and "lower alkynyl" indicate both straight-andbranched-chain hydrocarbon groups containing from one to six carbonatoms. Examples of such groups include methyl, ethyl, vinyl, allyl,ethynyl, propynyl and the like. Lower alkoxy groups contain in the alkylportion thereof from one to six carbon atoms. Examples of such groupsinclude methoxy, ethoxy, propoxy and the like. The term "lower alkanoyl"indicates those groups containing up to seven carbon atoms such as, forexample, acetyl, propionyl and the like. Further in accordance with theinvention, the term "cycloalkyl" indicates a cyclic hydrocarbon groupcontaining from three to seven carbon atoms such as, for example,cyclopropyl, cyclohexyl and the like.

The following group of compounds is especially preferred in accordancewith the present invention:

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7S)-7-methoxy-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-7-[2-(thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-ethyl-1,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-7-(2-cyanoacetamido)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(3-sydnonyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(1-tetrazolyl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-mandelamido]-3-cephem-4-carboxylicacid;

(7R)-7-[(R)-2-amino-2-phenylacetamido]-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxyhexanamido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxy-4-methyl-valeramido]-3-cephem-4-carboxylicacid;

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxy-2-(cyclohexyl-acetamido]-3-cephem-4-carboxylicacid; and

(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-furyl)-acetamido]-3-cephem-4-carboxylicacid.

In accordance with the present invention, the compounds represented byformula I are prepared by reacting a compound represented by the generalformula

    X'--W.sub.1                                                II

wherein X' is a deacetoxycephalosporin moiety, the carboxyl group atposition four thereof being in a protected form and W₁ is a leavinggroup with a compound represented by the general formula

    H--S--Y                                                    III

wherein X has the meaning given above and cleaving off the protectinggroup.

A second preparation in accordance with the present invention consistsof reacting a compound represented by the general formula

    X"--S--Y                                                   IV

wherein Y has the meaning given above and X" is adeacetoxycephalosporanyl group wherein the carboxyl group at positionfour is in a protected form with an acid represented by the generalformula

    Z--OH                                                      V

wherein Z represents an acyl group which is the substituent on the aminogroup in the 7 position of the deacetoxycephalosporinyl grouprepresented by X in formula I or with a reactive functional derivativethereof, and thereafter cleaving off the protecting group. If desired,the product may then be converted into a salt by conventional methods.

Examples of methods whereby the carboxyl group of the moiety representedby X' and X" in formulas II and IV can be protected by salt formationwith an inorganic or tertiary organic base such as, for example,triethylamine. After the reaction of the compounds of formulae II and IVwith the compounds of formulae III and V, respectively, is completed,the protecting group can be removed by methods well known in the art.Where the carboxyl group is protected by salt formation, e.g., withtriethylamine, the protecting group can be cleaved by treatment withacids such as, for example, hydrochloric acid, sulfuric acid, phosphoricacid, citric acid and the like at low temperatures, e.g., 0°-10° C.

Examples of the leaving group designated W₁ in formula II above includea halogen, e.g., chlorine, bromine or iodine, an acyloxy group such as,for example, a lower alkanoyloxy group such as acetoxy, a loweralkylsulfonyloxy group such as, for example, mesyloxy an arylsulfonyloxygroup such as, for example, tosyl, an azido group and the like.

The reaction of a compound of formula II with a compound of formula IIIis carried out utilizing methods well known in the art. Thus, thereaction is carried out at a temperature between about 40° C. and 80°C., preferably at about 60° C. in water or a buffer solution of pH 6 to7, preferably 6.5, for from 3 to 8, preferably 6, hours.

The reaction of a compound of formula IV with an acid of formula V or areactive functional derivative thereof can likewise be carried out byconventional procedures. For example, a free acid of formula V isreacted with an ester of formula IV in the presence of a carbodiimidesuch as, for example, dicyclohexyl carbodiimide or an oxazolium saltsuch as, for example, N-ethyl-5-phenylisoxazolium-3'-sulfonate. Further,a salt of an acid of formula IV, e.g., a trialkylammonium salt, can bereacted with a reactive functional derivative of an acid of formula V.These reactions are carried out in an inert organic solvent such as, forexample, ethyl acetate, acetonitrile, dioxane, chloroform, methylenechloride, benzene or dimethylformamide at a temperature of between about-40° and +5° C., preferably at 0° C.

Reactive functional derivatives of the acids of formula V include, forexample, halides, i.e., chlorides, bromides and fluorides, azides,anhydrides, particularly mixed anhydrides with strong acids, reactiveesters, e.g., N-hydroxysuccinimide esters, amides, e.g., imidazolidesand the like.

The compounds of formula II above are known and can be prepared bymethods known in the art from the corresponding cephalosporins, i.e.,compounds represented by the general formula

    X--O--CO--CH.sub.3

wherein X is as defined above. Examples of such compounds include thealkali metal salts, e.g., the sodium salts of cephalothin,7-alpha-methoxycephalothin, cephacetrile,(7R)-mandelamino-cephalosporanic acid and7-(3-syndnonacetamido)-cephalosporanic acid and the zwitter-ioncephaloglycine.

Certain of the compounds of formula III are novel. The novel compoundsof formula III can be prepared in a manner analogous to the preparationof the known compounds. Thus, a 1-substituted 2-oxo-4-mercaptopyridinecan be prepared from a correspondingly-substituted4-chloro-2-oxo-pyridine [Chem. Ber. 99, 255 (1966)] by nucleophilicexchange, e.g., with an alkali hydrogen sulfide. In a similar manner, a1,3-disubstituted-2,6-dioxo-1,2,3,6-tetrahydro-4-mercaptopyrimidine canbe prepared from a corresponding4-chloro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine. The5,6-dioxo-3-mercapto-as-triazines can be prepared from thecorrespondingly-substituted thiosemicarbazides in an analogous manner tothe synthesis of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine (see thedissertation of K. H. Ongania [Innsbruck 1972]). Finally, a thiol offormula III which contains a double-bond between the carbon atomsubstituted by the mercapto group and an adjacent nitrogen atom can bepresent as a tautomeric thioketone.

A compound of formula IV can be prepared by the reaction of a compoundrepresented by the formula

    X"--W.sub.1

wherein X" and W₁ have the meanings given above with a compound offormula III under the conditions given above for the reaction ofcompounds of formulas II and III.

The acids of formula V and their reactive derivatives are known or areanalogs of known compounds which can be prepared by conventional methodsknown to the art. The acids of formula V which contain an asymmetriccarbon atom normally occur as racemic mixtures which can be separatedinto optically active isomers by conventional procedures. For example,an optically active resolving agent such as alpha,alpha-(1-naphthyl)-ethylamine or alpha-methylbenzylamine which reactwith the carboxyl group can be utilized to form diastereomers which canbe separated by selective crystallization and converted into thecorresponding optical isomers.

The compounds of formula I can likewise occur as optically pure isomersand as isomeric mixtures. A compound of formula I in the D form can beprepared by the conventional procedure of fractional crystallization ofa salt such as the calcium salt or by reacting a compound of formula IIIwith a compound of formula II in the D form or a compound of formula IVwith an acid of formula V in the D form or a reactive functionalderivative thereof. The latter method is preferred.

The compounds of formula I possess a broad spectrum of antibioticactivity against both gram-positive and gram-negative microorganisms.Their antibiotic and bactericidal activity allows them to be usedtherapeutically and as disinfectants. The compounds of formula I areparticularly advantageous against penicillinase-positive Staphylococcias well as various cephalosporinase-positive gram-negative bacteria suchas, for example, Escherichia coli and various species of Proteus,Klebsiella, Aerobacter and Serratia. It is contemplated, in the case ofadults, a daily dosage of from about 1 to 4 grams is administeredparenterally. This dosage regimen may be adjusted by the clinician asthe therapeutic situation requires. The novel cephalosporin derivativesof the invention may also be administered orally, rectally or topicallyin suitable dosage forms and may be administered in the form of theirpharmaceutically acceptable salts or hydrates. Parenteral administrationis particularly preferred.

The compounds of formula I containing a free basic group, e.g., an aminogroup, form addition salts with organic and inorganic acids. Typicalorganic salts include, for example, alkylsulfonates, e.g.,ethanesulfonates, monoarylsulfonates, e.g., toluenesulfonates andbenzenesulfonates, acetates, tartrates, maleates, citrates, benzoates,salicylates, ascorbates and the like. Typical inorganic salts include,for example, the hydrohalides, e.g., hydrochloride and hydrobromide,sulfates, nitrates, phosphates and the like. The salts can also behydrated, either during manufacture or by gradual hydration of aninitially anhydrous salt due to the hydroscopic properties thereof.

The antimicrobial activity of two compounds representative of thecompounds of formula I against E. coli and penicillin resistant andpenicillin sensitive strain of Staphylococci is given in the followingtable. The results represent CD₅₀ values in the mouse upon subcutaneousinjection. In the table, compound A is(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylicacid sodium salt and compound B is(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylicacid sodium salt. The acute toxicity of these compounds (LD₅₀ i.v. inthe mouse) is between 2000 and 4000 mg/kg for compound A and between1000 and 2000 mg/kg for compound B.

                  TABLE                                                           ______________________________________                                               Staphylococcus                                                                              Staphylococcus                                                  aureus Schoch aureus 887    Escherichia                                Cmpd.  (Penicillin-sensitive)                                                                      (Penicillin-sensitive)                                                                      coli 1346                                  ______________________________________                                        A      0.25          5.5           0.38                                       B      0.60          3.2           0.90                                       ______________________________________                                    

The compounds of formula I and their pharmaceutically acceptable saltscan be used in the form of conventional pharmaceutical preparations; forexample, the aforesaid compounds can be mixed with conventional organicor inorganic, inert pharmaceutical carrier materials suitable forparenteral or internal administration. They can be administered inconventional pharmaceutical forms, preferably parenteral forms, forexample, solutions, suspensions and emulsions. Most preferably, thecephalosporins of the invention are prepared in a dry form, e.g., bylyophilization, suitable to be reconstituted for parenteraladministration. Examples of conventional pharmaceutical carriermaterials which may be utilized in such forms include, for example,water for injection, vegetable oils, polyalkylene glycols and the like.Such preparations can be subjected to conventional pharmaceuticalexpedients such as sterilization and can contain conventionalpharmaceutical adjuncts such as preservatives, stabilizing agents,wetting agents, emulsifying agents, salts for the adjustments of osmoticpressure, buffers and the like. The compositions can also contain othertherapeutically active materials.

The following Examples further illustrates the invention. Alltemperatures are in degrees centigrade.

EXAMPLE 1

A total of 120 g of 4-ethyl-thiosemicarbazide were reacted in thepresence of 23 g of sodium in 1 liter of methanol for 4 hours with 116 gof oxalic acid dimethyl ester at the boiling point of the mixture. Theproduct was isolated from the mixture as the sodium salt. The mixturewas then acidified and1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-astriazine was obtainedin aqueous solution, melting point 189°-190°.

4.4 Grams of cephalothin sodium [[α]_(D) ²⁰ =+130° (c=1 in water)] werestirred in 100 ml of water with 2.25 g of the1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine obtainedabove and 1.05 g of sodium bicarbonate for 6 hours at 60° and pH ca 6.5under a nitrogen atmosphere. The mixture was then cooled to 10° andadjusted to pH 2 with 2-N hydrochloric acid. The precipitate wasfiltered off under suction, washed with 25 ml of ice-water, dissolved inacetone and the resulting solution evaporated in vacuo. The residue wasdissolved in dimethylformamide and the solution treated with 7.5 ml of a2-N solution of the sodium salt of 2-ethyl-caproic acid in ethylacetate. By dilution with ethyl acetate, the desired productcrystallized out. The crystalline product was filtered off undersuction, washed successively with ethyl acetate, ether and petroleumether and dried in vacuo to yield 4.5 g (80%) of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; melting point 170° (decomposition); [α]_(D) ²⁰ =+13.1° (c=0.800 inwater).

EXAMPLE 2

In a manner analogous to that described in Example 1, 1.91 g of1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine, mp218°-220° (decomp.) prepared from 4-methylthiosemicarbazide and oxalicacid were reacted with 4.18 g of cephalothin sodium salt to yield 2.8 g(54.1%) the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6,-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; melting point 200°-205° (decomposition); [α]_(D) ²⁰ =-2.7°(c=0.592 in water).

EXAMPLE 3

In a manner analogous to that described in Example 1 3.33 g of1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-3-mercapto-as-triazine, mp138°-140°, prepared from 4-allyl-thiosemicarbazide and oxalic aciddimethyl ester were reacted with 6.29 g of cephalothin sodium salt toyield 3.0 g (36.8%) of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-allyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; melting point 180° (decomposition); [α]_(D) ²⁰ =+19.7° (c=0.376 inwater).

EXAMPLE 4

In a manner analogous that the described in Example 1 3.62 g of1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-3-mercapto-as-triazine, mp180°-181°, prepared from 4-butyl-thiosemicarbazide and oxalic aciddimethyl ester, were reacted with 6.27 g of cephalothin sodium salt togive the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-butyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl-acetamido]-3-cephem-4-carboxylicacid; melting point 160° (decomposition); [α]_(D) ²⁰ =+17.6° (c=0.640 inwater).

EXAMPLE 5

In a manner analogous to that described in Example 1 3.65 g of1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-3-mercapto-as-triazine,mp 158°-160°, prepared from 4-(2-methoxyethyl)-thiosemicarbazide andoxalic acid dimethyl ester were reacted with 6.27 g of cephalothinsodium salt to yield 2.0 g (23.8%); of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-(2-methoxyethyl)-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid (c=0.280 in water).

EXAMPLE 6

In a manner analogous to that described in Example 1 2.6 g of1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-3-mercapto-as-triazine, mp231°-233° (decomposition), prepared from 1,4-dimethyl-thiosemicarbazideand oxalic acid dimethyl ester were reacted with 6.27 g of cephalothinsodium salt to yield 4.6 g (58.0%) of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-1,4-dimethyl-5,6-dioxo-as-triazin-3-yl)-thio]-methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid); [α]_(D) ²⁰ =-9.55° (c=0.461 in water).

EXAMPLE 7

In a manner analogous to that described in Example 1 2.01 g of1,4,5,6-tetrahydro-1,4-diethyl-5,6-dioxo-3-mercapto-as-triazine, mp177°-170°, prepared from 1,4-diethyl-thiosemicarbazide and oxalic aciddimethyl ester were reacted with 6.27 g of cephalothin sodium salt toyield 5.5 g (65.7%) of the sodium salt of(7R)-3-[[1,4,5-6-tetrahydro-1,4-diethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; melting point 175° (decomposition); [α]_(D) ²⁰ =+10.2° (c=0.547 inwater).

EXAMPLE 8

A total of 46.5 g of 1-ethyl-thiosemicarbazide were reacted in 700 ml ofacetone at 40° with 48 g of oxalic acid monomethyl ester chloride. 34.3Grams of the product were treated with 9.2 g of sodium methylate in 300ml of methanol. The triazine was isolated from the mixture as the sodiumsalt. The mixture was then acidified and1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-3-mercapto-as-triazine obtained inaqueous solution; melting point 213°-214° (decomposition).

In a manner analogous to that described in Example 1 10.45 g ofcephalothin sodium salt were reacted with 4.8 g of the triazine obtainedabove to yield 7.0 g (52.6%); of the sodium salt of(7R)-3-[[(1,2,5,6-tetrahydro-1-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; melting point 210°-215° (decomposition); [α]_(D) ²⁰ =+8.85°(c=0.181 in water).

EXAMPLE 9

In a manner analogous to that described in Example 1 5.16 g of7-α-methoxy-cephalothin sodium salt [[α]_(D) ²⁰ =+194.5° (c=0.308 inwater)] was reacted with 1.82 g of1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-3-mercapto-as-triazine to give(7S)-7-methoxy-3-[[(1,4,5,6-tetrahydro-4-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt to yield 1.0 g (15.9%); [α]_(D) ²⁰ =+54.6°(c=0.308 in water).

EXAMPLE 10

In a manner analogous to that described in Example 1 4.18 g ofcephalothin sodium salt was reacted with 1.8 g of1-ethyl-1,2-dihydro-4-mercapto-2-oxo-pyrimidine to give(7R)-3-[[(1-ethyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylicacid as the sodium salt to yield 3.2 g (65.3%); melting point>190°(decomposition); [α]_(D) ²⁰ =-58) (c=0.570 in water).

EXAMPLE 11

In a manner analogous to that described in Example 1 4.18 g ofcephalothin sodium salt was reacted with 2.2 g of1-butoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine, mp 99°-100°, preparedfrom of 1-butoxyuracil and phosphorus pentasulfide; to yield(7R)-3-[[(1-butoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 3.8 g (70%); [α]_(D) ²⁰ =-6° (c=0.850 inwater).

EXAMPLE 12

In a manner analogous to that described in Example 1 25 g of1-butoxy-5-methyl-uracil prepared by reacting of butoxyurea withβ,β-diethoxy-α-methylpropionic acid ester was reacted with 50 g ofphosphorus pentasulfide to give1-butoxy-1,2-dihydro-4-mercapto-5-methyl-2-oxo-pyrimidine;

In a manner analogous to that described in Example 1 3.36 g of thethus-obtained pyrimidine was reacted with 6.0 g of cephalothin sodiumsalt to give(7R)-3-[(1-butoxy-1,2-dihydro-5-methyl-2-oxo-4-pyrimidinyl)-thio]methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid; yield 0,8 g (9,7%); melting point>170° (decomposition).

EXAMPLE 13

In a manner analogous to that described in Example 1 4.18 g ofcephalothin sodium salt were reacted with 1.8 g of1,4-dimethyl-1,6-dihydro-2-mercapto-6-dihydro-2-mercapto-6-oxo-pyrimidineto give(7R)-3-[[(1,4-dimethyl-1,6-dihydro-6-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt to yield 1.35 g (26.3%); melting point 200°-210°(decomposition); [α]_(D) ²⁰ =+9.5° (c=0.348 in water).

EXAMPLE 14

18 Grams of N-ethyl-thiourea were dissolved in 50 m. of glacial aceticacid, boiled to reflux and treated dropwise with 17.2 g of diketene. Themixture was then boiled at reflux for 20 minutes and subsequentlyevaporated to 50 ml. While cooling and stirring, the residue was treatedwith 50 ml of water. The yellowish crystals which precipitated werefiltered off under suction and recrystallized from tetrahydrofuran togive 1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine; meltingpoint 190°.

In a manner analogous to that described in Example 1, 6.27 g ofcephalothin sodium salt were reacted with 2.98 g1-ethyl-1,4-dihydro-2-mercapto-6-methyl-4-oxo-pyrimidine, to give(7R)-3-[[(1-ethyll,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt to yield 3.2 g (40.4%); melting point 170°(decomposition); [α]_(D) ²⁰ =14.4° (c=0.333 in methanol).

EXAMPLE 15

In a manner analogous to that described in Example 1 9.5 g ofcephacetrile sodium salt was reacted with 5.46 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine to give(7R)-7-(2-cyanacetamido)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid as the sodium salt to yield 3.3 g (26.8%); [α]_(D) ²⁰ =+7.85°(c=0.1785 in water).

EXAMPLE 16

In a manner analogous to that described in Example 1 8.0 g of the sodiumsalt of (7R)-mandelamido-cephalosporanic acid and 3.72 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine were reactedto give(7R)-3-[[1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-mandelamido]-3-cephem-4-carboxylicacid as the sodium salt to yield 1.7 g (16.8%); [α]_(D) ²⁰ =-19.6°(c=0.500 in water).

EXAMPLE 17

In a manner analogous to that described in Example 1 8.1 g ofcephaloglycine and 3.78 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine were reactedto yield 4.19 g (40.5%); of(7R)-7-[(R)-2-amino-2-phenylacetamido]-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid which was isolated as a Zwitter ion; yield 4.19 g (40.5% meltingpoint>180° (decomposition); [α]_(D) ²⁰ =-86.3) (c=0.276 indimethylformamide).

EXAMPLE 18

In a manner analogous to that described in Example 1 7.7 g of the sodiumsalt of 7-(3-sydnonacetamido)-cephalosporanic acid and 3.46 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine were reactedto give(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; to yield 3.3 g (31%); melting point>210°(decomposition): [α]_(D) ²⁰ =+17.9° (c=0.380 in water).

EXAMPLE 19

In a manner analogous to that described in Example 1 11.6 g of thesodium salt of 7-(3-sydnonacetamido)-cephalosporanic acid and 4.7 g of1-ethyl-1,2-dihydro-4-mercapto-2-oxo pyrimidine were reacted to give(7R)-3-[[(1-ethyl-1,2,-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 3.6 g (23.2%); [α]_(D) ²⁰ =-43.7°(c=0.600 in water).

EXAMPLE 20

A total of 2.72 g of 7-amino-cephalosporanic acid was suspended in 100ml of water together with1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine. Thesuspension was treated with 1.85 g of sodium bicarbonate to yield asolution having a pH of 6.4. The solution was stirred for 3 hours at 60°while gassing with nitrogen, then cooled to 20° and stirred undernitrogen for a further 1 hour with addition of 1 g of active carbon.After filtration, the filtrate was adjusted to pH 3.8 with 2-Nhydrochloric acid, cooled to 0° and stirred for 1 hour. The crystalswhich separated were filtered off under suction, washed successivelywith a small amount of ice-water, acetone, ether and petroleum ether anddried at 50° in a high vaccum to give7-amino-3-desacetoxy-3-[(1,4-5,6-tetrahydro-4-ethyl-4,6-dioxo-astriazine-3-yl)-thio]-cephalosporanic acid; yield 2.3 g (60%) of beigepowder of melting point 230°-235° (decomposition).

In an alternate synthesis of the above compound 5.1 g of7-amino-3-azido-3-desacetoxy-cephalosporanic acid were stirred for 6hours at 60° while gassing with nitrogen, together with 5.16 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 4.2 g ofsodium bicarbonate in 200 ml of a buffer of pH 7.0. The solution wascooled to 25° and adjusted to pH 3.5 with 2-N hydrochloric acid. Thecrystals which separated were filtered off under suction (2.2 g).Concentration of the mother liquor yielded a further 1.7 g; total yield3.9 g (50%).

1.28 Grams of tetrazole-1-acetic acid were dissolved in a mixture of 50ml of tetrahydrofuran and 5 ml of dimethylformamide. The resultingsolution was treated at -20° successively with 1.18 ml ofN-methyl-morpholine and 1.4 ml of chloroformic acid isobutyl ester andsubsequently stirred for 20 additional minutes at a temperature between-10° and -20°. To this mixture was added an ice-cold solution in 50 mlof water of the salt obtained by reacting 3.85 g of7-amino-3-descacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid and 1.4 ml of triethylamine. The mixture was then stirred for 30minutes at 0° and for 1 hour at 20°. Subsequently, the mixture wasconcentrated in vacuo and the aqueous phase acidified with 5 ml of 2-Nhydrochloric acid. whereby the product precipitated out as a crude acid.The latter was filtered off under suction, washed with excess ethylacetate and dissolved in dimethylformamide. The solution was treatedwith a 2-N solution of the sodium salt of 2-ethyl-caproic acid in ethylacetate and subsequently diluted with ethanol and ether, whereby thedesired crude sodium salt (3.3 g) precipitated out. For purification,the crude sodium salt was dissolved in 20 ml of water and treated with60 ml of ethanol, after which a dark resin precipitated and wasrejected. The filtrate was evaporated in vacuo and the residue treatedwith ethanol and ether to yield 2.3 g (44.5%) of pure(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt as a light-beige powder, melting point 210°(decomposition); [α]_(D) ²⁰ =+23° (c=0.824 in water).

EXAMPLE 21

4,4 Grams of7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid were dissolved at 0° in a mixture of 44 ml of water and 44 ml ofacetone by the addition of 2.5 g of potassium bicarbonate with stirring.There was then added dropwise at 0° while stirring, a solution of 3 g of(R)-2-dichloroacetoxy-n-caproic acid chloride (boiling point₀.5=75°-76°) in 30 ml of acetone. The mixture was then stirred for 2 hoursat 0° and for 1 hour at 20°. The acetone was distilled off from thefiltered solution at 30° under reduced pressure. The aqueous solutionwas stirred for 45 minutes at pH 9.5 by the addition of potassiumcarbonate, then extracted twice with ethyl acetate and adjusted to a pHof 1.5-2.0 with 3-N sulfuric acid. After extraction with ethyl acetatewith addition of dimethylformamide, the ethyl acetate solution waswashed several times with a 10% sodium chloride solution, dried overmagnesium sulfate and evaporated under reduced pressure at 25°. Theresidue was dissolved in 100 ml of isopropanol and treated with 12 ml ofa 2-N solution of the sodium salt of 2-ethyl caproic acid inisopropanol. The desired crude sodium salt was filtered off undersuction, reprecipitated from water/isopropanol and dried under reducedpressure. The pure sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxyhexanamido]-3-cephem-4-carboxylicacid was obtained as a bridge powder; yield 56%; melting point from 183°(decomposition); [α]_(D) ²⁵ =+8.2° (c=1.00 in water).

EXAMPLE 22

In a manner analogous to that described in Example 21 3.5 g of7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid were reacted with 2.4 g of (R)-2-dichloroacetoxy-isocaproic acidchloride (boiling point ₀,2 =63°-64°) to yield;(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxy-4-methylveleramido]-3-cephem-4-carboxylicacid as the sodium salt yield 51%; melting point from 180°(decomposition); [α]_(D) ²⁵ =+6.0° (c=1.00 in water).

EXAMPLE 23

In a manner analogous to that described in Example 21 3.9 g of7-amino-3-desacetoxy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid were reacted with 2.9 g of(R)-2-dichloroacetoxy-2-cyclohexyl-acetyl chloride (boiling point₀.5=105°.107°)*(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxy-2-cyclohexyl-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 37%; melting point from 190°(decomposition); [α]_(D) ²⁵ =+2.8° (c=0.50 in water).

EXAMPLE 24

3.85 Grams of7-amino-3-desacetoxy-3-[1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-61)-thio]-cephalosporanicacid were dissolved at 0° in a mixture of 40 ml of water and 40 ml ofacetone by the addition of 2.4 g of potassium bicarbonate and stirring.To this solution there was added dropwise at -5°, a solution of 1.45 gof 2-(2-furyl)-acetyl chloride in 15 ml of acetone and the mixturestirred for 3 hours at -5° and for 1.5 hours at 20°. The solution wasextracted twice with ethyl acetate and the aqueous phase acidified at 0°with 3-N sulfuric acid to a pH value of 2. After extraction with ethylacetate with addition of dimethylformamide, the ethyl acetate solutionwas washed three times with a 10% sodium chloride solution, dried overmagnesium sulfate and evaporated under reduced pressure at 25°. Theresidue was dissolved in methanol and treated with 8 ml of a 2-Nsolution of the sodium salt of 2-ethyl-caproic acid in isopropanol. Thedesired crude sodium salt was precipitated with diethyl ether, filteredoff under suction, washed with diethyl ether and then recrystallizedfrom water with addition of acetone. There was obtained(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-furyl)acetamido]-3-cephem-4-carboxylicacid as the sodium salt, a beige powder: yield 43%; melting point from180° (decomposition); [α]_(D) ²⁵ =+18.4° (c=1.0 in water).

EXAMPLE 25

In a manner analogous to that described in Example 1 8.36 g ofcephalothin sodium salt were reacted with 3.0 g of1-amino-1,2-dihydro-4-mercapto-2-oxo-pyridine to give(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 4.1 g (40.2%); melting point>185°(decomposition); [α]_(D) ²⁰ =78.5° (c=0.439 in water).

The pyrimidine was prepared by reacting 1-benzylideneaminouracil[melting point 220°-223°]; Literature: Monatshefte fur Chemie 96, 1735(1965) with 12 g of phosphorus pentasulfide in pyridine, followed byhydrolysis with hydrochloric acid.

EXAMPLE 26

In a manner analogous to that described in Example 1 8.26 g ofcephalothin sodium salt were reacted with 3.34 g of1,2,5,6-tetrahydro-5,6-dioxo-3-mercapto-2-methyl-as-triazine to give(7R)-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 5.8 g (56%); melting point 185°(decomposition); [α]_(D) ²⁰ =-49.3 (c=0.450 in water). The triazine wasprepared in a manner analogous to that described in Example 1 byreacting 31.5 g of 2-methyl-thiosemicarbazide and 35.4 g of oxalic aciddimethyl ester; melting point 260°.

EXAMPLE 27

In a manner analogous to that described in Example 1 8.26 g ofcephalothin sodium salt were reacted with 2.98 g of1,2-dihydro-4-mercapto-1-methyl-2-oxo-pyrimidine to give(7R)-3-[[(1,2-dihydro-1-methyl-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 7.3 g (62.4%); melting point 180°(decomposition); [α]_(D) ²⁰ =-67.7° (c=0.604 in water).

EXAMPLE 28

In a manner analogous to that described in Example 1 8.36 g ofcephalothin sodium salt were reacted with 3.32 g of1,3-dihydro-4-mercapto-1-methoxy-2-oxo-pyrimidine to give(7R)-3-[[(1,2-dihydro-1-methoxy-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; [α]_(D) ²⁰ =-90.6° (c=0.338 in water). Thepyrimidine was prepared in a manner analogous to that described inExample 11 by reaction of 1-methoxyuracil and 18 g of phosphoruspentasulfide; melting point 177°.

EXAMPLE 29

In a manner analogous to that described in Example 1 6.27 g ofcephalothin sodium salt were reacted with 2.75 g of1-ethoxy-1,2-dihydro-4-mercapto-2-oxo-pyrimidine to give(7R)-3-[[(1-ethoxy-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 3.5 g (44%); melting point 180°(decomposition); [α[_(D) ²⁰ =-74.2° (c=0.525 in water). The pyrimidinestarting material was prepared in a manner analogous to that describedin Example 11 by reacting 6.4 g of 1-ethoxyuracil and 18 g of phosphoruspentasulfide; melting point 119°-120°.

EXAMPLE 30

In a manner analogous to that described in Example 1 1.25 g ofcephalothin sodium salt were reacted with 0.470 g of1,6-dihydro-3-mercapto-1-methyl-6-oxo-pyridazine to give(7R)-3-[[(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 1.0 g (66.7%); melting point>215°(decomposition); [α]_(D) ²⁰ =-49.7° (c=0.332 in water). The pyridazinestarting material was prepared by reacting 2.88 g of3-chloro-1,6-dihydro-1-methyl-6-oxo-pyridazine [melting point 91°-92°];Literature: Monatshefte fur Chemie 99, 33 (1968)] and 5.88 g of sodiumhydrosulfide in ethanol at 130° and 5-7 atmospheres; melting point 115°.

EXAMPLE 31

In a manner analogous to that described in Example 20 9.5 g ofsydnono-3-acetic acid were reacted with 21.4 g of7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-oxo-pyrimidin-4-yl)-thio]cephalosporanicacid to give(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(3-sydnonyl)acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 9.7 g (32%); melting point from 200°(decomposition); [α]_(D) ²⁰ =-61.3° (c=0.5 in water).

EXAMPLE 32

In a manner analogous to that described in Example 1 24.5 g ofD-p-hydroxy-N-tert.butyl-oxycarbonyl-cephaloglycine were reacted with8.66 g of 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazinewith subsequent removal of the tert.butyloxycarbonyl protecting groupwith formic acid to give(7R)-7-[(R)-2-amino-2-(p-hydroxyphenyl)-acetamido]-3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid; yield 5.7 g (23%); melting point from 200° (decomposition);[α]_(D) ²⁰ =79.8° (c=0.3 in dimethylformamide).

EXAMPLE 33

In a manner analogous to that described in Example 1 6.0 g of cephapirinwere reacted with 2.56 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine to give(7R)-3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(4-pyridyl-thio)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 1.9 g (26%); melting point form 205°(decomposition); [α]_(D) ²⁰ =+36.2° (c=0.5 in water).

EXAMPLE 34

In a manner analogous to that described in Example 1 6 g of(pyrazol-1-yl-methyl)-cephalosporin sodium salt were reacted with 3.12 gof 1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine to give(7R)-3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-(2-pyraczol-1-yl-acetamido)-3-cephem-4-carboxylicacid as the sodium salt; yield 4.0 g (51%); melting point from 190°(decomposition).

EXAMPLE 35

A solution of 76 g of thiourea in 1000 ml of dimethylformamide wastreated with 65.4 ml of methyl isocyanate and then stirred for 72 hoursat 50°-55°. The solution was then evaporated in vacuo and the residuerecystallized from water; yield 79.5 g (60%) of colourless5-methyl-2-thio-biuret melting point 209°-210°.

A solution of 14.8 g of sodium in 1000 ml of methanol was treated with39.9 g of 5-methyl-2-thio-biuret and 72 g of diethylcarbonate and boiledat reflux for 25 hours. The solution was concentrated to a volume of 200ml in vacuo. The substance which crystallized out was filtered off undersuction, dissolved in 200 ml of water and acidified with 2-Nhydrochloric acid. The precipitated compound was filtered off undersuction and recrystallized from 350 ml of ethanol; yield 11.2 g (23%) ofcolorless substance; melting point 275°.

In a manner analogous to that described in Example 1 8.36 g ofcephalothin sodium salt were reacted with 3.34 g of1,2,3,6-tetrahydro-2,6-dioxo-4-mercapto-1-methyl-s-triazine preparedabove to give(7R)-3-[[(1,2,3,6-tetrahydro-2,6-dioxo-1-methyl-s-triazin-4-yl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt yield 5.5 g (53%); melting point from 220°(decomposition); [α]_(D) ²⁰ =-43° (c=0.1 in water).

EXAMPLE 36

44 Grams of N-ethylurea and 105 g of β,β-diethoxypropionic acid ethylester were added to a solution of 15.0 g of sodium in 700 ml of ethanol.The yellow solution was then heated for 3 hours at 25° and subsequentlyboiled under reflux for 15 hours. The mixture was evaporated in vacuoand the residue dissolved in 300 ml of water, cooled to 0° and acidifiedwith 100 ml of concentrated hydrochloric acid. A crystallineintermediate precipitated out (43 g) and was filtered off under vacuum,washed with 100 ml of ice-water and subsequently heated to 80°-100° in250 ml of water until conversion into the desired water-soluble1-ethyl-uracil is complete. The solution was evaporated in vacuo at 40°and the remaining residue recrystallized from ethanol/ether; yield 14.0g (20%) of colorless 1-ethyl-uracil; melting point 150° C.

Chlorine was led into a solution of 9.9 g of 1-ethyl-uracil in 150 ml ofglacial acetic acid until iodine-potassium-starch paper reactedpositively and 1-ethyl-uracil was no longer detectable by thin-layerchromatography (ca. 0.5 hours). The mixture was evaporated in vacuo at40° and the crystalline residue recrystallized from 300 ml of ethanol;yield 10.0 g (81%) of colorless, fine needles of 1-ethyl-5-chlorouracil;melting point 244°-247°.

1.74 Grams of 1-ethyl-5-chlorouracil were mixed with 4.44 g ofphosphorus pentasulfide and 0.1 ml of water and the mixture treated with30 ml of pyridine and boiled at reflux for 3.75 hours. The mixture wasthen evaporated in vacuo at 40°, the residue suspended in 30 ml of waterand treated with 30 ml of 2-N hydrochloric acid. The crystals obtainedwere filtered off under suction, washed with water and recrystallizedfrom 1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine; meltingpoint 217°-220°.

In a manner analogous to that described in Example 1 6.27 g ofcephalothin sodium salt were reacted 3.04 g of1-ethyl-5-chloro-1,2-dihydro-4-mercapto-2-oxo-pyrimidine prepared aboveto give(7R)-3-[[(1-ethyl-5-chloro-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 3.5 g (42%); melting point from 185°(decomposition); [α]_(D) ²⁰ =-95.2° (c=0.394 in water).

EXAMPLE 37

In a manner analogous to that described in Example 20 2.95 g oftetrazol-1-acetic acid were reacted with 8.55 g of7-amino-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid to give(7R)-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 4.65 g (40%); melting point 220°-230°(decomposition); [α]_(D) ²⁰ =53.6° (c=0.321 in water).

EXAMPLE 38

In a manner analogous to that described in Example 21 9.25 g ofD-O-dichloroacetyl-mandelic acid chloride were reacted with 11.1 g of7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid to give(7R)-7-(R)-mandelamido-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl-thio]methyl]-3-cephem-4-carboxylicacid as the sodium salt; yield 4.3 g (27%); melting point 200°-210°(decomposition); [α]_(D) ²⁰ =66.8° (c=0.296 in water).

EXAMPLE 39

In a manner analogous to that described in Example 20 5.76 g ofsydnono-3-acetic acid were reacted with 14.95 g of7-amino-3-desacetoxy-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid to give(7R)-7-[2-(3-sydnonyl)-acetamido]-3-[[(1,2,5,6-tetrahydro-2-methyl-5-,6-dioxo-as-triazine-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid as the sodium salt; yield 7.0 g (33%); melting point from 200°(decomposition); [α]_(D) ²⁰ =-25.5° (c=0.227%).

EXAMPLE 40

In a manner analogous to that described in Example 1 3.34 g ofcephalothin sodium salt were reacted with 1.42 g of of1,2-dihydro-1-dimethylamino-4-mercapto-2-oxo-pyrimidine to give;(7R)-3-[[(1-dimethyl-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 2.4 g (57%); melting point from 165°(decomposition); [α]_(D) ²⁰ =-65.2° (c=0.557 in water).

EXAMPLE 41

67.75 Grams of 3,4-dichloro-6-hydroxy-pyridazine were dissolved in 205ml of a 2-N sodium hydroxide solution and treated dropwise with 36 ml ofdimethylsulfate. The mixture was then heated at 70° for 0.5 hour, cooledand extracted twice with chloroform. The combined chloroform extractswere washed with water, dried over sodium sulfate and evaporated invacuo. The residue is recrystallized from high boiling petroleum ether;yield 54 g of 3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine (73%);melting point 97°.

A solution of 17.9 g of the3,4-dichloro-1,6-dihydro-1-methyl-6-oxo-pyridazine prepared above in 200ml of methanol was treated with a solution of 14.8 g of sodiumhydrosulfide monohydrate in 200 ml of methanol. The mixture was thenstirred for 1.5 hours at 25° while gassing with nitrogen. Undissolvedmaterial was then filtered off and the filtrate concentrated in vacuo.The residue was suspended in 150 ml of water, made acidic with 1-Nhydrochloric acid and extracted three times with ethyl acetate. Thecombined ethyl acetate extracts were washed with water, dried oversodium sulfate and evaporated in vacuo. The residue obtained wasrecrystallized from ethanol; yield 9 g of yellowish needles of3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxopyridazine; melting point163°.

In a manner analogous to that described in Example 1 8.36 g ofcephalothin sodium salt were reacted with 3.7 g of3-chloro-1,6-dihydro-4-mercapto-1-methyl-6-oxo-pyridazine prepared aboveto give(7R)-3-[[3-chloro-1,6-dihydro-1-methyl-6-oxo-4-pyridazinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; melting point 225°-230° (decomposition);[α]_(D) ²⁰ =+5.35° (c=0.522 in water).

EXAMPLE 42

In a manner analogous to that described in Example 1 7.55 g ofcephalothin sodium salt were reacted with 2.95 g of1,2-dihydro-1,6-dimethyl-4-mercapto-2-oxopyridine to give(7R)-3-[[(1,2-dihydro-1,6-dimethyl-2-oxo-4-pyridyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 3.0 g (31%); melting point 178°-185°(decomposition); [α]_(D) ²⁰ =+46.2° (c=0.353 in water).

EXAMPLE 43

In a manner analogous to that described in Example 1 8.24 g ofcephaloram sodium salt were reacted with 3.63 g of1,4,5,6,-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine to give(7R)-3-[[(4-ethyl-1,4,5,6-tetrahydro-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-(2-phenylacetamido)-3-cephem-4-carboxylicacid as the sodium salt; yield 2.2 g (21%); melting point 190°-200°(decomposition); [α]_(D) ²⁰ =+19.8° (c=0.339 in water).

EXAMPLE 44

The(7R)-7-[(RS)-2-bromo-2-phenylacetamido]-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl-3-cephem-4-carboxylicacid sodium salt was prepared in a manner analogous to that described inExample 21 from 23.1 g of7-amino-3-desacetopy-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporanicacid and 14.0 g of DL-α-bromophenylacetic acid chloride; yield 10 g(28%); melting point from 190° (decomposition).

EXAMPLE 45

23.7 Grams of 1-ethyl-3-chloro-1,2-dihydro-2-oxo-pyrazine were added toa solution of 22.2 g of sodium hydrosulfide monohydrate in 1000 ml ofmethanol and the mixture stirred for 3 hours at 25°. The precipitatedsodium chloride was then filtered off and the yellow filtrate evaporatedin vacuo at 40°. The residue was recrystallized from ethanol; yield 8.0g (34%) of crude yellow substance. For purification, 5.0 g of the latterwere suspended in 50 ml of 0.5-N hydrochloric acid and stronglyacidified with addition of 10 ml of 2-N hydrochloric acid. The mixturewas stirred for 10 minutes at 25° and subsequently stored overnight in arefrigerator.

The resulting orange-yellow crystals1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine (3.65 g) were filtered offunder bacuum, washed with a small amount of ice-water and dried in vacuoat 50°; melting point 204°-206° (decomposition).

In a manner analogous to that described in Example 1 6.27 g ofcephalothin sodium salt were reacted with 2.50 g of1-ethyl-1,2-dihydro-3-mercapto-2-oxo-pyrazine prepared above to give(7R)-3-[[(1-ethyl-1,2-dihydro-2-oxo-3-pyrazinyl)-thio]methyl]-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid as the sodium salt; yield 5.0 g (65%); melting point from 175°(decomposition); [α]_(D) ²⁰ =+12.2° (c=0.5 in water).

EXAMPLE 46

4.0 grams of(7R)-3-azidomethyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid sodium salt [melting point from 170° (decomposition); [α]_(D) ²⁰=+134.4° (c=0.5 in water)] 2.07 g of1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-3-mercapto-as-triazine and 1.01 gof sodium bicarbonate were combined in 100 ml of a buffer solution of pH7.0 and stirred for 24 hours at 50°-55° while gassing with nitrogen.

The mixture was then cooled to 25° and adjusted to pH 2 with 2-Nhydrochloric acid. The crude acid which precipitated was filtered offunder suction, washed with water and then stirred for 10 minutes in 100ml of ethyl acetate. The purified acid was filtered of under suction(1.3 g), suspended in 25 ml of methanol and treated with 2.5 ml of a 2-Nsolution of 2-ethylcaproic acid sodium salt in ethyl acetate, a solutionresulting. By dilution with 100 ml of ethyl acetate, the sodium salt of(7R)-3-[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)thio]methyl-7-[2-(2-thienyl)-acetamido]-3-cephem-4-carboxylicacid precipitated out; yield 1.25 g (24%); identical in allcharacteristics with the product manufactured according to Example 1.

EXAMPLE 47

In a manner analogous to that described in Example 20 6,4 g(tertrazolyl)-acetic acid and 17,75 g7-amino-3-desacetoxy-3-[(1-amino-1,2-dihydro-2-dihydro-2-oxopyrimidin-4-yl)-thio]-cephalosporanicwere reacted to give(7R)-3-[[(1-amino-1,2-dihydro-2-oxo-4-pyrimidinyl)-thio]-methyl]-7-[2-(1-tetrazolyl)-acetamido]-4-carboxylicacid as the sodium salt; yield 8.0 g (33%); melting point from 190°(decomposition).

EXAMPLE 48

Reconstitutable preparations for intramuscular injection were preparedby lyophilizing and hermetically sealing ampoules each containing 2,5 mlof a sterile solution of 1 gram of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxoas-triazin-3-yl)-thio]methyl]-7-[2-(1-H-tetrazol-1-yl)-acetamido]-3-cephem-4-carboxylicacid. The contents of the ampoule are reconstituted with 2.5 ml of asterile 2% solution of lidocaine hydrochloride before prior toadministration.

EXAMPLE 49

Ampoules were prepared according to the manner described in Example 47containing 1 gram of the sodium salt of(7R)-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[2-(5-oxo-1,2,3-oxadiazolidin-3-yl)-acetamido]-3-cephem-4-carboxylicacid.

We claim:
 1. A compound of the formula: ##STR2## wherein Y is a5,6-dioxo-as-triazin-3-yl group where at least one nitrogen atom in saidtriazinyl group is substituted with a member selected from the groupconsisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,hydroxyl, lower alkoxy, amino, mono(lower alkyl)amino, di(loweralkyl)amino, formyl lower alkanoyl, lower alkanoylamino, carbamoyl,mono(lower alkyl)aminocarbonyl and di(lower alkyl)aminocarbonyl; R₁ ishydrogen or methoxy, R₃ is hydrogen, hydroxy, hydroxymethyl, amino,azido, carboxy or sulfo; R₂ is cyano, or a substituent selected from thegroup consisting of pyridylthio, alkyl containing from 1 to 6 carbonatoms, alkenyl containing from 2 to 6 carbon atoms, saturated orunsaturated non-aromatic cyclic hydrocarbon containing from 3 to 6carbon atoms, phenyl, phenylalkyl or phenoxyalkyl wherein saidsubstituent can be unsubstituted or substituted with one or more membersselected from the group consisting of hydroxy, halo, lower alkyl orlower alkoxy; with the proviso that when R₂ is pyridylthio, R₃ ishydrogen; and pharmaceutically acceptable salts thereof and hydratesthereof.
 2. A compound of the formula: ##STR3## wherein R₁ is loweralkyl; R₂ is phenyl or phenyl substituted with hydroxy, halo, loweralkyl having 1 to 3 carbon atoms, or lower alkoxy containing 1 to 4carbon atoms; and R₃ is hydrogen, hydroxy, sulfo, amino or carboxy orsalts thereof.
 3. A compound of the formula: ##STR4## wherein Y is a5,6-dioxo-as-triazin-3-yl group where at least one nitrogen atom in saidtriazinyl group is substituted with a member selected from the groupconsisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl,hydroxy, lower alkoxy, amino, mono(lower alkyl)amino, di(loweralkyl)amino, formyl lower alkanoyl, lower alkanoylamino, carbamoyl,mono(lower alkyl)aminocarbonyl and di(lower alkyl)aminocarbonyl; orpharmaceutically acceptable salts thereof and hydrates thereof.
 4. Thecompound of claim 3 wherein Y is a 1,2,5,6-tetrahydro-2-loweralkyl-5,6-dioxo-as-triazin-3-yl.
 5. The compound of claim 4 wherein saidcompound is7-amino-3-desacetoxy-3[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)-thio]-cephalosporonicacid or salts thereof.
 6. A compound in accordance with claim 1 whereinsaid compound is (7R)-7-(2-Cyanoacetamido)-3-[[(1,4,5,6-tetrahydro-4l-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid.
 7. A compound in accordance with claim 1 wherein said compound is(7R)-3-[[(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-mandelamido]-3-cephem-4-carboxylicacid.
 8. A compound in accordance with claim 1 wherein said compound is(7R)-7-[(R)-2-Amino-2-phenylacetamido]-3-[[(1,4,5,6-tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-3-cephem-4-carboxylicacid.
 9. A compound in accordance with claim 1 wherein said compound is(7R)-3-[[(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxyhexanamido]-3-cephem-4-carboxylicacid.
 10. A compound in accordance with claim 1 wherein said compound is(7R)-3-[[(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-2-hydroxy-4-methyl-valeramido]-3-cephem-4-carboxylicacid.
 11. A compound in accordance with claim 1 wherein said compound is(7R)-3-[[(1,4,5,6-Tetrahydro-4-ethyl-5,6-dioxo-as-triazin-3-yl)-thio]methyl]-7-[(R)-7-hydroxy-2-(cyclohexyl)acetamido]-3-cephem-4-carboxylicacid.
 12. The compound of claim 1 wherein said compound is(7R)-7-(R)mandelamido-3-[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]-methyl3-chem-4-carboxylic acid or pharmaceutically acceptable salts thereof.13. A compound of claim 3 having the formula: ##STR5## wherein R₁ islower alkyl or salts thereof.